Pharmacodynamic properties of methotrexate and Aminotrexate™ during weekly therapy

Peter D. Cole, María José Alcaraz, Angela K. Smith, John Tan, Barton A. Kamen

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

4-amino-pteroyl-glutamic acid (Aminotrexate™; AMT) has several advantages over the related antifolate methotrexate (MTX), including greater potency, complete oral bioavailability, and greater accumulation by leukemic blasts in vitro. We compared the pharmacodynamic properties of AMT (given orally at 4 mg/m2 in two divided doses per week) and MTX (100 mg/m 2 in four divided doses per week) among children with acute lymphoblastic leukemia. We find AMT and MTX to have equivalent penetration into the bone marrow compartment of these patients, as indicated by the steady-state concentrations within mature red blood cells (RBCs). However, MTX concentrations in the cerebrospinal fluid after oral dosage are significantly greater than AMT. To confirm these clinical observations, mice were treated four weekly injectons of AMT or MTX, at a 1:20 dosage ratio, and tissue antifolate content was then determined over the subsequent 22 days. We confirm the selective exclusion of AMT from the CNS compartment, while showing equivalent accumulation of AMT and MTX in the RBCs, liver, spleen, kidneys and testes. Finally, we demonstrate that AMT, MTX, and their predominant polyglutamate species are equipotent inhibitors of their target intracellular enzyme dihydrofolate reductase, emphasizing the critical nature of steady-state tissue accumulation in determining the relative cytotoxic potency of these two antifolates.

Original languageEnglish (US)
Pages (from-to)826-834
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume57
Issue number6
DOIs
StatePublished - Jun 2006
Externally publishedYes

Fingerprint

Pharmacodynamics
Methotrexate
Folic Acid Antagonists
Therapeutics
Blood
Erythrocytes
Tissue
Polyglutamic Acid
Cerebrospinal fluid
Tetrahydrofolate Dehydrogenase
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Liver
Biological Availability
Cerebrospinal Fluid
Testis
Glutamic Acid
Bone
Spleen
Bone Marrow
Cells

Keywords

  • Acute lymphoblastic leukemia
  • Aminopterin
  • Methotrexate
  • Neurotoxicity
  • Polyglutamates
  • Rheumatoid arthritis

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Pharmacodynamic properties of methotrexate and Aminotrexate™ during weekly therapy. / Cole, Peter D.; Alcaraz, María José; Smith, Angela K.; Tan, John; Kamen, Barton A.

In: Cancer Chemotherapy and Pharmacology, Vol. 57, No. 6, 06.2006, p. 826-834.

Research output: Contribution to journalArticle

Cole, Peter D. ; Alcaraz, María José ; Smith, Angela K. ; Tan, John ; Kamen, Barton A. / Pharmacodynamic properties of methotrexate and Aminotrexate™ during weekly therapy. In: Cancer Chemotherapy and Pharmacology. 2006 ; Vol. 57, No. 6. pp. 826-834.
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